ABSTRACT Patients with the myeloproliferative neoplasms (MPNs) Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) suffer progressive cytopenias, bone marrow fibrosis and/or transformation to acute leukemia. The identification of somatic activating mutations in the JAK-STAT pathway in the majority of MPN patients led to the clinical development of JAK kinase inhibitors. Although they provide important clinical benefit, current JAK inhibitors do not show disease-modifying activity in most patients. In addition, recent studies have shown that mutations in the chromatin modifier ASXL1 are associated with adverse clinical outcome in PMF. These data underscore the need novel therapeutic approaches for MF patients based on mechanistic insight into disease pathogenesis. We propose to investigate the mechanisms by which JAK2 and ASXL1 mutations cooperate to induce myeloid transformation, and to investigate novel therapeutic approaches in MF. This will include studies which evaluate the impact of concurrent JAK-STAT pathway and ASXL1 mutations on MPN pathogenesis, progression and therapeutic resistance to targeted therapies. We will also investigate the role of novel therapeutic approaches, specifically type II JAK2 inhibitors and combined signaling/epigenetic therapies targeting JAK2 and LSD1/BRD4 in MF murine models and primary patient samples. The studies in this project will leverage novel, genetically accurate murine models coupled with detailed studies of primary samples from the MPN-RC sample bank. Most importantly, the studies in this project are aimed to credential novel therapeutic approaches which can then be transitioned to the clinic for near-term mechanism based clinical trials.